Abstract
The clinically important MAM blood group antigen is present on haematopoietic cells of all humans except rare MAM-negative individuals. Its molecular basis is unknown. By whole-exome sequencing we identify EMP3, encoding epithelial membrane protein 3 (EMP3), as a candidate gene, then demonstrate inactivating mutations in ten known MAM-negative individuals. We show that EMP3, a purported tumour suppressor in various solid tumours, is expressed in erythroid cells. Disruption of EMP3 by CRISPR/Cas9 gene editing in an immortalised human erythroid cell line (BEL-A2) abolishes MAM expression. We find EMP3 to associate with, and stabilise, CD44 in the plasma membrane. Furthermore, cultured erythroid progenitor cells from MAM-negative individuals show markedly increased proliferation and higher reticulocyte yields, suggesting an important regulatory role for EMP3 in erythropoiesis and control of cell production. Our data establish MAM as a new blood group system and demonstrate an interaction of EMP3 with the cell surface signalling molecule CD44.
Highlights
The clinically important MAM blood group antigen is present on haematopoietic cells of all humans except rare MAM-negative individuals
The reactivity of anti-MAM was not characteristic of a CD44-related antibody, this was the only indication of a potential association of MAM with a known red cell membrane protein and this relationship was explored further in the monoclonal antibody-specific immobilisation of erythrocyte antigens (MAIEA) assay
Our results suggest a role for epithelial membrane protein 3 (EMP3) in stabilising CD44 in the erythroblast plasma membrane
Summary
The clinically important MAM blood group antigen is present on haematopoietic cells of all humans except rare MAM-negative individuals. By wholeexome sequencing we identify EMP3, encoding epithelial membrane protein 3 (EMP3), as a candidate gene, demonstrate inactivating mutations in ten known MAM-negative individuals. Blood group antigens are carried by functional proteins, glycoproteins and glycolipids at the erythrocyte membrane surface and are defined by specific antibodies that recognise a polymorphism of a commonly expressed molecule. Epithelial membrane protein 3 (EMP3) is a member of the peripheral myelin protein 22 (PMP22)/claudin superfamily of proteins, a protein family characterised by the members each having four transmembrane domains with two extracellular loops and one short intra-cellular loop[5]. This study demonstrates that EMP3 is expressed on erythrocytes and is the carrier molecule for the MAM antigen, establishing MAM as a new blood group system
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